Comparing clinical outcomes of ARB and ACEi in patients hospitalized for acute COVID-19

Continued receipt of Renin–Angiotensin–Aldosterone inhibitors in patients with COVID-19 has shown potential in producing better clinical outcomes. However, superiority between ACEi (angiotensin-converting enzyme inhibitors) and ARB (angiotensin II receptor blockers) regarding clinical outcomes in this setting remains unknown. We retrospectively collected data on patients hospitalized for acute COVID-19 using the nationwide administrative database (Diagnosis and Procedure Combinations, DPC). The DPC data covered around 25% of all acute care hospitals in Japan. Patient outcomes, with focus on inpatient mortality, were compared between patients previously prescribed ACEi and those prescribed ARB. Comparisons based on crude, multivariate and propensity-score adjusted analysis were conducted. We examined a total of 7613 patients (ARB group, 6903; ACEi group 710). The ARB group showed lower crude in-hospital mortality, compared to the ACEi group (5% vs 8%; odds ratio, 0.65; 95% CI 0.48–0.87), however not in the multivariate-adjusted model (odds ratio, 0.95; 95% CI 0.69–1.3) or propensity-score adjusted models (odds ratio, 0.86; 95% CI 0.63–1.2). ARB shows potential in reducing hospital stay duration over ACEi in patients admitted for COVID-19, but does not significantly reduce in-hospital mortality. Further prospective studies are needed to draw a definitive conclusion, but continuation of either of these medications is warranted to improve clinical outcomes.


Methods
Study population. The current study used the largest nationwide hospital administrative database, called diagnosis and procedure combination (DPC) data in Japan, from 25% (438 of 1750) of all acute care hospitals. The majority of middle to large-sized hospitals are part of the DPC register. The DPC dataset used in the current study was collected from the Ministry of Health, Welfare, and Labour of the government of Japan by the Medical Data Vision (MDV), Co., Tokyo, Japan (As of April 1, 2021) 14 . The MDV DPC dataset covers DPC hospitals throughout Japan, and the age and gender distribution of registered patients are comparable to the distribution of patients at healthcare institutions nationwide as published by the government of Japan, thus is a fair representation of the national data 14 . Recent studies on COVID-19 used data of an MDV DPC dataset 15,16 . The current study collected the MDV DPC data from 1 January 2010 to 30 November 2021 and included patients of all ages with confirmed (RT-PCR test positive) acute COVID-19 (International Classification of Diseases and Related Health Problems, 10th Revision diagnosis code U071) who required admission with acute COVID-19 as the major cause of admission. Data from the first such admission was used in the current study.
Data collection. The MDV DPC dataset for our analysis included patients' demographics (age and gender), diagnoses, comorbidities, prescriptions, and procedures as well as clinical data including outcomes (e.g., in-hospital mortality) and length of hospital stay. Patients on ACEi or ARB were identified as those who were prescribed these medications within 30 days prior to the date of admission related to acute COVID-19. Patients on neither ACEi nor ARB were excluded. Patients on both ACEi and ARB were excluded from analysis because this combination is not recommended in any clinical scenario. Our data included demographics, smoking history, body mass index, baseline disease, and confirmed presence of critical conditions at the time of admission by physicians (shock, coma, or cardiorespiratory failure). Baseline disease data were identified and collected using ICD-10 coding based on the previous study that used MDV DPC data 15 . Since there was data missing for smoking history and body mass index, multiple imputations with chained equations were used to utilize data of all available admitted patients 15 . Our data also included complications (acute respiratory distress syndrome [ARDS], etc.), treatment modalities, requirement for oxygen therapy, invasive mechanical ventilation or renal replacement therapy (RRT), as well as in-hospital mortality and length of hospital stay. In the DPC database, information on prescribing physicians' characteristics for ACEi or ARB (specialty, age, gender) was unavailable.
The current study was approved by the Muribushi Okinawa Ethics Committee.

Statistical analyses.
Regarding baseline characteristics, continuous variables were described as mean and standard deviation, while nominal variables as count and proportion. Logistic or linear regression models were employed to examine the association between outcomes (in-hospital mortality and requirement of invasive mechanical ventilation, or renal replacement therapy, and length of hospital stay) and the use of ACEi or ARB. The models were constructed by crude comparison, adjusted analysis for baseline clinical characteristics (including age, gender, obesity, referral from another institution, ischemic heart disease, heart failure, arrythmia, hypertension, dementia, dyslipidemia and iron deficiency anemia), and propensity score analyses (score adjusted). The propensity score analysis was conducted based on the method of previous studies 17, 18 . On analysis of RRT, chronic kidney disease was omitted from variables for adjustment because of interaction to ARB. Patients with hemodialysis before admission (n = 108; ARB = 106, ACEi = 2) was excluded for analysis in RRT. Analyses were conducted using STATA version 15 (NC, US). A p-value less than 0.05 was defined as statistically significant.

Results
Baseline characteristics. Between January 2020 and November 2021, 67,348 inpatients were diagnosed with COVID-19, 7613 patients of which were receiving either ARB or ACEi (ARB group = 6193, ACEi group = 710) and were included in the study. Compared to patients on ACEi, those on ARB were more likely to be younger, women, obese, hypertensive, or suffering from chronic kidney disease (CKD grade 5D). Meanwhile, the ACEi group was more likely to have a history of ischemic heart disease, heart failure, arrhythmia, dementia, or iron deficiency anemia (Table 1). There was no statistically significant difference in smoking history, history of diabetes mellitus, cerebrovascular disease, chronic kidney disease (except CKD grade 5D), peripheral vascular disease, liver cirrhosis or cancer.
The difference in treatment and complication of hospitalized patients with COVID-19 between ARB and ACEi. As shown in Table 2, the ARB group was more likely to receive dexamethasone or other glucocorticoids and renal replacement therapy (RRT, including patients on hemodialysis before admission) while less likely to receive invasive mechanical ventilation (IMV), extracorporeal membrane oxygenation, vasopressors or blood transfusion. There was no statistically significant difference in the proportion of oxygen therapy, non-invasive positive pressure therapy or renal replacement therapy in patients without hemodialysis before admission (165/6797 [2.4%] vs 13/708 [1.8%]). In terms of the short-term complication of COVID-19 (in 30 days after the diagnosis of COVID-19), patients on ARB were less likely to experience deep vein thrombosis (DVT) and acute ischemic heart disease (aIHD) or atrial fibrillation/flutter. While no difference was observed in septic shock, acute kidney injury (AKI), disseminated intravascular coagulation (DIC), pulmonary embolism (PE), cardiopulmonary arrest (CPA), acute myocarditis, subarachnoid/intracranial hemorrhage (SAH/ICH) or brain infarction (BI). As long-term complications (30 days or more after COVID-19 diagnosis), ARB groups experienced less DVT, and no statistically significant difference was observed in other complications (septic shock, AKI, PE, CPA, aIHD, SAH/ICH or BI). The proportion of acute respiratory distress syndrome (ARDS) after admission was lower in the ARB group. ), but multiple logistic regression analyses and analysis based on propensity score showed no difference in in-hospital mortality between the ARB and ACEi groups ( Table 3). The ARB group showed lower crude odds of ARDS but not in adjusted models. In the ARB group, the odds of aIHD was lower in crude and propensity score analysis. Prevalence of IMV in crude, multivariate and propensity score analysis by baseline characteristics such as past medical history was lower in ARB patients  Tables 2, 3), which was still significant after multivariate or propensity score adjustment. (Table 3).

Discussion
To the best of our knowledge, our study comprising of 7613 patients with acute COVID-19, is the first large-scale study of its kind to directly compare clinical outcomes between ACEi and ARB, while other available clinical studies are limited to hypotheses based on indirect comparisons. Our results showed that in crude analysis, those receiving ARB had a lower rate of in-hospital mortality, however, no superiority between the two was seen www.nature.com/scientificreports/ after adjustments for age, gender, obesity, referral from another institution, ischemic heart disease, heart failure, arrythmia, hypertension, dementia, dyslipidemia, and iron deficiency anemia. Notably, in secondary analysis, significant reduction in hospital stay duration was seen in the ARB group in both adjusted and unadjusted analysis. This may be partly explained by the fact the ARB group was associated with reduced risk of multiple clinical outcomes, with unadjusted risk reduction in deep vein thrombosis and atrial arrhythmia observed, while unadjusted and adjusted risk reduction seen for acute ischemic heart disease and invasive mechanical ventilation, without statistically significant difference for acute respiratory distress syndrome. A recent study suggested that ACEIs were associated with increased odds of sepsis in COVID-19 patients, while ARBs were not 19 . In addition to vasodilation, ARBs mediate anti-inflammatory effects 20 , which may contribute to better outcomes among COVID-19 patients. In a meta-analysis of 7 randomized controlled trials, the use of ACEi/ARB in COVID-19 patients was not associated with a higher risk of mortality (risk ratio [RR] = 0.84, 95% CI 0.57-1.22, p = 0.10, I2 = 43%). Moreover, in the same study, compared with no ACEi/ARB use, ARBs were associated with a significant decrease in mortality ([RR] = 0.23, 95% CI 0.09-0.60, p = 0.55, I2 = 0%) and disease severity ([RR] = 0.38, 95% CI 0.19-0.77, p = 0.007), hinting indirectly at potential superiority to ACEi 21 . In another recent prospective study that included 566 hypertensive patients with acute COVID-19, reduced risk of in-hospital mortality in those receiving ARB to those receiving other blood pressure lowering agents was demonstrated, further hinting indirectly at potential superiority to ACEi 22 . Although a definitive conclusion cannot be drawn, our findings are in line with these studies, pointing further at possible benefit of ARBs in this clinical setting. Significant differences in baseline characteristics between the two groups were seen, most notably, those on ACEi were more likely to be suffering from cardiac complications including ischemic heart disease, heart failure and arrhythmia. Multiple professional cardiology societies (including the American Heart Association, American College of Cardiology, European Society of Cardiology) recommend the use of ACEi to reduce the risk of developing symptomatic heart failure and mortality in those with LVEF ≤ 40%, with ARBs reserved for those who are intolerant to ACEi. This is suggestive of the fact that those on ACEi are more likely to already suffer from cardiac disease, thereby relatively decreasing the risk of developing acute ischemic heart disease (aIHD) in the ARB group, as is shown in our results. Patients on NPPV were rarely seen in both groups, likely due to the national Japanese guideline on COVID-19 published during this period recommending against the use of NPPV to address the possible risk of aerosols being contaminated with SARS-CoV2 particles.
There are several limitations to our study. First, our study is of retrospective nature, and a further prospective study that directly compares ACEi and ARB is needed for a more definitive conclusion. Second, the baseline population was considerably greater in the ARB group which may have led to selection bias and outcomes may Table 3. Comparison of unadjusted, adjusted, fully adjusted and propensity score adjusted clinical outcomes between patients with ARB compared to ACEi. OR odds ratio, RRT renal replacement therapy. Logistic regression was implemented for analysis of mechanical ventilation and in-hospital mortality, and linear regression was employed for comparing length of hospital stay. "Multivariate adjusted" analysis was adjusted for age, male sex, obesity (Body mass index over 30), referral from another healthcare institution and comorbidities (hypertension, chronic kidney disease, ischemic heart disease, heart failure, arrhythmia, dementia, dyslipidemia and iron deficiency anemia). Propensity score was calculated from following variables: age, male sex, obesity (Body mass index over 30), referral from another healthcare institution and comorbidities (hypertension, ischemic heart disease, heart failure, arrhythmia, dementia, dyslipidemia and iron deficiency anemia). In analysis of RRT, chronic kidney disease was omitted from variables for adjustment because of interaction to ARB. Patients with hemodialysis before admission (n = 108; ARB = 106, ACEi = 2) was excluded for analysis in RRT. www.nature.com/scientificreports/ be disproportionate despite propensity-matched analysis. Although propensity-score matching and multivariable regression models were utilized in the statistical analysis to account for measured confounders, due to the study's observational nature, some confounders may exist that may not have been accounted for. As mentioned above, the ACEi population were more likely to be suffering from multiple comorbidities especially heart disease which may hint towards a sicker baseline population, yet we were unable to match propensity scores completely which may have resulted in potentially biased results. Third, we were unable to extract data on antibiotic prescriptions between the two groups which may introduce a source of potential confounding, therefore, results should be interpreted with caution. Fourth, our DPC data does not cover the entire Japanese population thus our results can only be interpreted as a substitute representation, therefore, a selection bias may exist within the study population.
It also remains to be seen whether the results are representative of smaller, rural populations. Lastly, information regarding vaccine status was not included in the analysis, which may have had an impact on clinical outcomes. In conclusion, among hypertensive patients hospitalized for COVID-19, ARB was associated with lower crude rate of in-hospital mortality, but not in adjusted analysis. The use of ARB has potential in improving clinical outcomes, but continuation of either ARB or ACEi is of utmost importance.

Data availability
The data that support the findings of this study are available from the Medical Data Vision, Co., but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Medical Data Vision, Co.